Prolonged release bioadhesive therapeutic systems

ABSTRACT

The present invention concerns a prolonged release bioadhesive mucosal therapeutic system containing at least one active principle, with an active dissolution test of more than 70% over 8 hours and to a method for its preparation. The bioadhesive therapeutic system may be in tablet form and may contain quantities of natural proteins representing at least 50% by weight of active principle and at least 20% by weight of the tablet, between 10% and 20% of a hydrophilic polymer, and compression excipients, and may contain between 4% and 10% of an alkali metal alkylsulphate to reinforce the local availability of active principle and between 0.1% and 1% of a monohydrate sugar.

This application is a Continuation of copending PCT InternationalApplication No. PCT/FR02/02635 filed on Jul. 23, 2002, which was notpublished in English and which designated the United States and on whichpriority is claimed under 35 U.S.C. § 120, the entire contents of whichare hereby incorporated by reference. This nonprovisional applicationclaims priority under 35 U.S.C. §119(a) on patent application No.0109811 filed in France on Jul. 23, 2001, which is herein incorporatedby reference.

FIELD OF THE INVENTION

The present invention relates to the medical field, in particular thefield of mucosal infections. More particularly, the present inventionrelates to novel prolonged release bioadhesive therapeutic systems fortreating local mucosal infections or the mucitis and candidiasis type.The invention also relates to methods for treating such symptoms and tonovel release forms for improving their efficacy. The bioadhesivetherapeutic systems of the invention can be used for curative orpreventative treatment of such disease types.

BACKGROUND OF THE INVENTION

Candidiasis is a disease resulting from a local proliferation of fungalspecies (Candida). Such proliferation can have a number of origins, inparticular a local physico-chemical imbalance (modification of pH, etc.)associated, for example, with taking antibiotics, steroids or otherphysical treatments (irradiation, chemotherapy, immunodepressors, etc.).The increase in immunodepression situations (related to immunodepressionconsecutive upon chemotherapy in the treatment of cancer or the AIDSepidemic) was the cause of a re-emergence of oral candidiasis and severeparodontal disease (Hermant et al., 1997, Med. Mal. Infect. 27:715-718).Buccal candidiases are routinely detected even in HIV seropositivesubjects who are apparently in good health. They are often the firstmanifestation of an HIV infection. More than 90% of patients with AIDSdevelop oral candidiasis (Vasquez, 1999, Pharmacotherapy, 19(1): 76-87).The prevalence approaches 20% in certain populations; it increases withthe reduction in the number of CD4 (Greenspan & Greenspan, 1996, Lancet348:729-733). Further, candidosa is a common characteristic of infectionby the immunodeficiency virus HIV and cancer. The fungal speciesresponsible for those candidiases are Candida such as C. albicans, C.glabrata, C. tropicalis or C. krusei.

Particular signs associated with candidiasis are dry mouth, pain oningestion, loss of taste, bums, etc. A change in the condition of thebuccal cavity has serious implications for the general condition of thepatient. Buccal infections that are poorly treated can be the cause ofodynophagia and dysphagia, can interfere with speech, mastication anddeglutition. Further, the pain caused by those infections leads patientsto reduce their food intake; this results in a loss of weight,dehydration and malnutrition. Prevention and treatment of oralcandidiasis is thus an essential concern in maintaining quality of lifeand in preventing more severe complications in those patients (Weinertet al., 1996, Amn. Intern. Med. 125: 485-496).

Candidiasis is also a frequent complication in anticancer treatments. Inparticular, chemotherapy, bone marrow graftings or local irradiation areall factors encouraging the development of local candidiasis typeinfections. The secondary oral effects of chemotherapy are a majorsource of morbidity in cancerology. Out of 27 clinical tests: 14 withmucitis (945 randomized cases) and 15 with oral candidiasis (1164randomized cases), the incidence of mucitis was 50% to 80% and that ofcandidiasis was 30% to 70% and varied as a function of the location ofthe cancer. In view of that analysis, partially absorbed treatmentsappear to be more effective than those which are totally absorbed by theintestinal tract as regards prophylaxis (Clarkson et al., 2000, CochraneDatabase Syst Rev. (2): CD000978).

More generally, a further factor encouraging the development ofcandidiasis is an alteration in the integrity of the mucosa, for exampleby local or diffuse desquamation. Mucitis is one of such conditions: itinvolves an erythema generally followed by local desquamation. Thealteration in the mucosa (generally buccal) that is induced is the earlystage forming the bed of infection, in particular a fungal infection inAIDS or cancer (chemotherapy, bone marrow grafting, local irradiationwith tumours to the head and neck, etc). Patients suffer locally fromsalivary hypofunction, which itself is responsible for an alteration indental hygiene (Greenspan et al., The Lancet 348 (1996) 729).

Candidosa infections are currently treated in the first intention in alocal manner, essentially using antifungals: magistral preparations,lozenges, mouthwashes, azoles, polyenes (Greenspan et al., Lancet 348:729-733). Azole derivatives are proposed in the second intention, bysystemic route, in the case of oesophageal candidiasis (ketoconazole,fluconazole, itraconazole). Such treatments are effective in preventionbut are risky (interactions with drugs, resistance, intolerance). Suchsystemic azoles are reserved for short therapies in confirmedcandidiasis (Kovacs et al., 2000, The New England Journal of Medicine,May 11, 1416-1429).

A further disadvantage of these treatments resides in frequentlyobserved relapses. Some studies observed 60% recurrence in the threemonths following treatment (Imam et al., Amer. J. of Medicine 89 (1990)142).

Considering the physiopathology of candidiasis, Candida albicans andalso C. krusei, C. tropicalis and C. glabrata are the agents responsiblefor the local infection (mouth, oesophagus, skin, nails, vagina). It canbe more or less profound depending on the host's defenses. It is acutanco-mucous affection that can induce complications and becomesystemic. Effective local treatment or preventing buccal candidiasis canavoid systemic candidiasis and the appearance of resistant strains.

Adhesion of the fungus to the mucosa is an essential element in itspathogenicity. The residency time of an antifungal product in the buccalcavity can be an essential element in its immediate and long termefficacy.

Described or existing formulations or compositions are based on formsfor systemic administration both as regards their galenic form and theactive principles involved.

The present invention provides a prolonged release bioadhesivetherapeutic system that is essential for producing a long residence timein the locations of the infection in contrast to the usual local forms(mouthwashes, gel, pastils, lozenges) which have a transitional effect.

By way of example, a buccal gel for local application based onmiconazole is sold by Janssen-cilag (92787 Issy-les-Moulineaux, France)under the trade name Daktarin buccal gel® for the treatment of mycosesof the buccal cavity. Miconazole is an antifungal from the imidazolefamily. It acts in situ after application. As it is only very slightlyre-absorbed, it is well tolerated. The dosage for treating buccalmycoses in adult is 125 mg of miconazole (two spoonfuls) applied 4 timesa day for 7 to 15 days. The salivary concentration of the miconazole isa good reflection of the efficacy of the product. It varies from 5 to0.4 μg/ml 30 minutes to 3 hours after applying the gel. Its very rapidreduction is explained by the very short residency time of gel in thebuccal cavity. Further, the MIC (minimum inhibitory concentration) ofmiconazole against Candidosa albicans is in the range 1 to 10 μg/ml(Daktarin monograph, medical information from the Swiss Compendium ofMedicinal Products). This concentration is only obtained achieved duringthe short period following application of the gel. As a result, theantimycotic coverage obtained with the buccal gel is mediocre.

Bioadhesive forms and their preparation method have been described inpatent EP-0 542 824 B1. They were designed for systemic passage andcannot be used for local action. They do not permit satisfactory invitro dissolution, a criterion for determining local availability. Thus,they are incompatible with using an active principle such as anantifungal which necessitates local action and/or limited systemicpassage.

SUMMARY OF THE INVENTION

The present invention is drawn to a prolonged release bioadhesivemucosal therapeutic system containing at least one active principle,having an active principle dissolution percentage of more than 70% over8 hours, comprising quantities of natural proteins representing at least50% by weight of active principle and at least 20% by weight of thebioadhesive therapeutic system, between 10% and 20% of a hydrophilicpolymer, compression excipients, and comprising between 3.5% and 10% ofan alkali metal alkylsulphate and between 0.1% and 1% of a monohydratesugar.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a typical production diagram for a tablet of the invention.

FIG. 2 shows an in vitro dissolution test for a tablet with twodifferent dosages (50 mg and 100 mg) containing sodium laurylsulphate ina concentration of 4.5%.

FIG. 3 shows the mean salivary concentration obtained with time formiconazole by comparing a tablet containing 50 mg of miconazole (blacktriangle), a tablet containing 100 mg of miconazole (white square) and agel containing miconazole sold under the trade name Daktarin® (whitecircles).

FIG. 4 shows the correlation between the salivary miconazole levelsexpressed in μg/ml and the percentage dissolution in vitro.

FIG. 5 show in vitro dissolution tests for 50 mg dose tablets ofaciclovir containing sodium laurylsulphate in a concentration of 4.5%and lactose or saccharose as a binder.

DETAILED DESCRIPTION OF THE INVENTION

The present invention aims to overcome all of the disadvantagesdescribed above by providing novel prolonged release bioadhesivetherapeutic systems by ensuring solubilisation of active principles toensure its local efficacy. Indeed, prolonged release forms can reducethe number of doses and produce more stable levels of active principleover time.

Throughout the text, the terms “bioadhesive” or “mucoadhesive” will beused equally, therapeutic systems of the invention are more particularlysuitable for mucosal administration.

Similarly, the term “therapeutic” encompasses both therapy andprophylaxis of the different pathologies mentioned above, and inparticular mucitis and candidiasis.

The bioadhesive therapeutic systems can be in the form of bioadhesivetablets, microspheres or nanospheres.

The present invention also provides a method for preparing saidbioadhesive therapeutic systems in the form of tablets with the desiredqualities for use on all types of mucosa.

More precisely, the bioadhesive tablets and methods of the invention aresuitable for treating mucitis and candidiasis in the context of diseasesin immunodepressed subjects (elderly, malnourished, antibiotherapy,cancer, AIDS, radiotherapy, chemotherapy, grafting).

Said tablets are also suitable for administering active principles forwhich mucosal administration has advantages as regards therapy orcomfort, compared with buccal, transdermal or systemic administration.As an example, it may be antivirals such as aciclovir, valaciclovir,ganciclovir, zidovudine or insoluble analgesics such as fentanyl base.

They enable favorable local use of insoluble or slightly soluble activeprinciples. They also enable a number of active principles to becombined in the tablet to increase compliance and acceptability of thetreatment, such as other antifungals with a different spectrum,analgesics, salivation agents, etc.

The tablets of the invention also enable that the dose can be reducedand thus, undesirable secondary effects which can accompany the normaluse of such drugs can also be reduced. Further, the invention alsodescribes compositions that are particularly advantageous clinically asthey are active on the basis of a single (or two) daily dose(s).Finally, their novel formulation does not alter taste and appetite,which are essential elements in maintaining a good general condition inthe immunodepressed patient.

The present invention also provides a solution to the disadvantages ofthe prior art, enabling a more complete and better tolerated control ofmucosal infections and associated symptoms (continuous and non-transientcover) and of certain viral diseases, pain or other diseases.

In a first aspect, the invention provides a prolonged releasebioadhesive mucosal therapeutic system containing at least one activeprinciple, having an active principle dissolution test of more than 70%over 8 hours, comprising quantities of natural proteins representing atleast 50% by weight of active principle and at least 20% by weight ofsaid bioadhesive therapeutic system, between 10% and 20% of ahydrophilic polymer, compression excipients to reinforce the hardness ofthe bioadhesive therapeutic system, and comprising between 4% and 10% ofan alkali metal alkylsulphate and optionally between 0.1% and 1% of amonohydrate sugar.

A particular embodiment of the mucosal bioadhesive therapeutic system ofthe invention is constituted by a mucoadhesive tablet.

The essential role of adding an alkali metal alkylsulphate is todissolve a low solubility or insoluble active principle and tofacilitate its local availability: the alkali metal alkylsulphate agentfacilitates systemic passage of the active principle as a function ofits concentration (Martin-Algarra, 1994, Pharmaceutical Research, (11),7: 1042-1047). In the formulation of the present invention, by formingmicelles, it acts as a solubilizing agent that does not facilitateabsorption. It also facilitates swelling and allows constant release ofthe active principle over 8 hours.

More particularly, the bioadhesive therapeutic systems of the inventionare suitable for preventing or treating buccal, oesophageal or vaginalinfections.

Still more particularly, they are suitable for preventing or treatingbuccal candidosal infections in immunodepressed patients. The tablets ofthe invention can be used in a curative or preventative manner. Further,the tablets of the invention are more particularly intended for buccaladministration but are also suitable for other forms of administrationby adapting the galenic form.

In summary, the bioadhesive therapeutic systems of the invention have anumber of major properties and advantages:

-   -   a formulation that allows ready dosage (compatible with        preventative or maintenance treatment) and optimum activity of        the active principles;    -   one or more other active principles and/or excipients can be        associated with the first active principle to ensure hydration        and good local acceptance of the compositions;    -   a dose of active principle that is substantially lower than that        used in other existing galenical forms can reduce or avoid        undesirable effects;    -   the salivary concentrations of active principle are higher than        the minimum inhibitory concentration (MIC) over a prolonged        period.

The bioadhesive therapeutic systems of the invention contain at leastone active principle.

When the bioadhesive therapeutic systems are intended to prevent andtreat fungal infections, a preferred active principle is a compound fromthe broad spectrum azole family preferably selected from miconazole,clotrimazole, ketoconazole, fluconazole, itraconazole, isoconazole,econazole, saperconazole, genaconazole, terconazole, butoconazole,tioconazole, oxiconazole, bifonazole, fenticonazole, omoconazole,sertaconazole, voriconazole and sulconazole. It is advantageouslytriazoles such as fluconazole, itraconazole or saperconazole; orimidazoles preferably selected from miconazole, clotrimazole andketoconazole.

Particularly preferred azole compounds in the present invention aremiconazole, ketoconazole and itraconazole, and unitary doses are then inthe range 10 to 150 mg per tablet.

A still more preferred compound is miconazole whose chemicaldenomination is(RS)-1-[-2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)-ethyl]-1H-imidazole,present in a dose of 10 to 150 mg per tablet, preferably 25 to 75 mg andmore preferably 50 mg per tablet.

Azole compounds are known to act on the synthesis of a constituent ofthe fungal membrane: ergosterol.

The bioadhesive therapeutic systems of the invention and containingsubstantially 50 mg per tablet ensure a continuous and prolongedpresence of the active principle above the MIC at the site of action ina single daily dose as well as the various advantages described above,and in the absence of systemic passage.

A further advantage of bioadhesive therapeutic systems essentiallycomprising 50 mg of miconazole is the excellent tolerance of the activeprinciple as the useful dose per day in the 50 mg preparation is tentimes lower than the usual dose of the same product in the referenceformulation, Daktarin buccal gel formulation (500 mg/d) whilesurprisingly, the local concentrations are considerably increased (7 to10). An important advantage is the reduction in the risk of acquiringresistance to the fungi. Indeed, the appearance of resistance to acompound often occurs if the local concentration is less than the MICallowing the yeast to grow again. The useful dose in the tablets of theinvention can also reduce or even eliminate certain undesirable effectsresulting from a dose of 500 mg/d, such as intestinal problems (nausea,vomiting, diarrhea) or allergic reactions. Transaminase elevations arerarely observed.

The various advantages of the bioadhesive therapeutic systems of theinvention will become clear from the following examples that essentiallydescribed the pharmaceutical forms and the results of comparativeclinical tests.

The azole miconazole type compound can be associated with a furtheractive principle selected, for example, from an antifungal with adifferent spectrum, of the polyene type, an analgesic, a salivationagent, a saliva substitute, an antiseptic, an anti-inflammatory(corticoid), thalidomide or a mixture thereof.

Polyenes have a different action mechanism to azoles. They bond tosterol groups, principally ergosterol, present in the fungal membraneand induce the appearance of pores and channels. These pores andchannels substantially increase cell permeability and the loss of smallmolecules, leading to cell death.

From polyenes, preferred polyenes for use in the compositions of theinvention are broad spectrum polyenes, preferably tetraenes. Nystatinand amphotericin B can in particular be cited.

Advantageously, nystatin is used in the bioadhesive therapeutic systemsof the invention.

Polyenes are advantageously used in doses in the range 10 to 100 mg,preferably in the range 20 to 90 mg. By way of illustration,amphotericin is advantageously used in doses in the range 20 to 60 mg.Nystatin is used in an amount of 10 mg to 100 mg, preferably 20 mg to 40mg, more preferably about 25 mg.

The doses can be recommended in units knowing that 1 mg corresponds to4400 units. A preferred composition of the invention comprises 50 to 400mg of an imidazole or triazole compound and 20 to 90 mg or 100 000 to200 000 units of a polyene. More preferably, the azole compound ismiconazole and the polyene is nystatin. The compositions of theinvention are generally intended for use in one or two daily doses.Preferably, they are administered at intervals that allow them to betaken daily in amounts of 20 to 200 mg of azole and 50 000 to 500 000units of polyene (10 to 110 mg).

Further, to improve the treatment efficacy, the bioadhesive therapeuticsystems of the invention applied to mucosal administration can alsocomprise one or more other active principles. More particularly, thebioadhesive therapeutic systems of the invention can comprise one ormore active principles that ensure hydration and local acceptance, anindication of compliance in this type of treatment. The use of this typeof active principle is particularly advantageous in acute applicationand in maintenance treatment.

The associated excipients and other active principles can, for example,advantageously be selected from one or more anaesthetic compounds,salivation agents, antiseptics, anti-inflammatories, thalidomide,antibiotics, saliva substitutes or flavour masking agents, used alone orin combination.

The combined use of an active principle with anaesthetic properties isparticularly advantageous since, as indicated above, candidiasis isoften accompanied by severe pain, in particular during ingestion. Anexample of a suitable anaesthetic for use in the context of theinvention is lidocaine or tetracaine. Preferably, the anaesthetic isused in doses in the range 0.1% to 10% of the total weight of the activeingredients of the compositions of the invention, more preferably in therange 1% to 7%.

A typical composition in accordance with the invention comprises about1% to 5% of anaesthetic, for example lidocaine.

The combined use of an agent facilitating salivation is alsoadvantageous for treating candidiasis, which frequently causes drymouth. In a further aspect, then, the invention concerns a bioadhesivetherapeutic system or a composition comprising at least one activeprinciple and a salivation agent.

The active principle can be an antifungal compound as described below,an antiviral for the treatment of HIV infections (human immunodeficiencyvirus), EBV (Epstein-Barr virus, infectious mononucleosis, hairyleukoplakia), CMV (cytomegalovirus), herpes simplex virus (HSV) or thevaricella zoster virus (VZV). The active principles contained in thebioadhesive therapeutic systems are then zidovudine, aciclovir,valaciclovir or ganciclovir. It can also be an insoluble or onlyslightly soluble analgesic for which other administration modes poseprecisely those solubility problems. An example that can be cited is lowsolubility fentanyl base which is important in treating severe resistantpain in particular associated with cancer.

An example of a suitable salivation agent for use in the context of theinvention is pilocarpine. Pilocarpine is currently used in treatingxerostomia in patients receiving irradiation when treating cancers ofthe head and neck. An example of another salivation agent isbethanechol.

The salivation agent is preferably used in doses in the range 0.1% to10% by weight of the total weight of the active constituents in thecompositions of the invention, more preferably between 0.1% and 5%.

A composition of the type defined in the invention comprises about 0.5%to 3% of a salivation agent, for example pilocarpine.

More preferably, a particular association of the invention comprises atleast one antifungal compound, an anaesthetic and a salivation agent.More preferably, an advantageous composition of the invention comprises:

-   -   25 to 75 mg of an imidazole or triazole compound;    -   1% to 7% by weight of an anaesthetic; and    -   0.1% to 5% by weight of a salivation agent.

Further, to improve observance of the treatment, a flavour masking agentcan be used if necessary, for example with antifungals. However, in adose of 50 mg of miconazole, the bioadhesive tablet is characterized byan absence of disagreeable flavour. This agent is preferably free ofsugar to avoid possible complications in the mouth, in particular dentalproblems (caries). In a further embodiment, the bioadhesive therapeuticsystems of the invention comprise at least one antifungal compound and aflavour masking agent. This latter comprises mentholated typederivatives, for example. The flavour masking agent is advantageouslyused in combination with the anaesthetic and the salivation agent asdescribed above.

Further, as indicated above, the combined use of an antiseptic also hasmajor advantages, in particular when used in prophylactic treatment orfor maintenance treatment. The use of this type of compound can ensurebetter oral hygiene for patients afflicted with candidiasis infections.In particular, the use of this type of agent can reduce the bacterialpopulations present in the oral cavity. A suitable antiseptic is eitherthe alkali metal alkylsulphate alone, or associated with chlorexidine (0to 5%), an antibiotic (fusafungin, 500 mg, for example) or with ananti-inflammatory, or with a corticoid.

The combined use of said symptomatic active principles endows thecompositions of the invention with supplementary properties, inparticular:

-   -   hydration of the mucosa and mouth;    -   masked flavour;    -   comfort in use (controlling pain);    -   better oral hygiene.

Thus, the present invention shows that it is possible to combine in theactive compositions different agents with complementary properties,ensuring more effective treatment of candidiasis infections in patients.In particular, the compositions of the invention allow global treatmentof these diseases, in contrast to early or local systemic treatmentsusing azoles, the efficacy of which is high but which can causeresistance.

The active principles used in the context of the invention can beconditioned in the same homogeneous or heterogenous bioadhesivetherapeutic system with two phases with two release rates, or separatelydepending on whether administration is carried out simultaneously or atintervals. Further, they can be formulated in different manners,depending on the nature of the compounds, and the dosage. Theformulation can be in the form of homogeneous or double-layer tablets,or in the form of micro- or nano-spheres. In general, packaging andformulation are defined to allow compatibility of the associatedproducts, reduced or facilitated administration frequency (one or twodoses a day), easy delivery system (preferably an oral bioadhesiveform), a masked taste if necessary, local hydration, an absence ofsystemic passage and good acceptability.

A further aspect of the bioadhesive therapeutic systems of the inventioncan be found in the excipients and the fillers. Adhesiveness isconferred by natural proteins, which represent at least 50% by weight ofthe active principle. Types of natural proteins that can be used arethose described in EP 0 542 824. A particular example is a milk proteinconcentrate titrating a minimum of 85% of proteins such as Prosobel L85,LR85F or, preferably either Promilk 852A sold by Armor Protéines, orfrom the Alaplex range (4850, 1180, 1380 or 1395) from NZMP. Therelative concentration of the natural proteins in a bioadhesive tabletof the invention is 15% to 50%, preferably 20% to 30%.

The bioadhesive therapeutic systems of the invention also compriseexcipients which are normal in bioadhesive systems, as will be shown inthe examples below.

A particular characteristic of the compounds of the invention is thatthey contain between 3.5% and 10% of a metal alkylsulphate. Preferably,it is selected from the group formed by sodium laurylsulphate anddiethylsulphosuccinate. More preferably, it is sodium laurylsulphate ina concentration of 4% to 6% by weight of the total tablet weight.

The presence of a dose of more than 3.5% of an alkali metalalkylsulphate and more particularly sodium laurylsulphate can, as willbe shown in the following examples, increase the release of miconazolefrom the tablet in vitro, namely more than 80% over 8 hours as opposedto the active principle being impossible to dissolve in the absence ofalkali metal alkylsulphate including over short periods. Thus, itincreases the solubility of insoluble or low solubility activeprinciples. This is essential to food availability of the activeprinciple locally. Further, it allows better swelling of the tablet,which has the advantage of producing a constant release of the activeprinciple into the site of action of pathogenic agents. It should benoted that such a concentration of sodium laurylsulphate associated withthe adhesive tablet is completely unusual for a tablet in which theconcentration of this product rarely exceeds 3%.

Thus in the present invention, the solubilizing function of the sodiumlaurylsulphate as regards a low solubility active principle has anessential role for its in situ liberation. The examples below indicategood coherence between the in vitro dissolution test and the cumulativesalivary concentration over time measured in vivo.

Thus, the presence of sodium laurylsulphate in a concentration of 4% to6% is an essential element in the composition of tablet and in thequalities of tablet cited above: good availability, a single dose perday, etc.

Sodium laurylsulphate in the minimum concentration of 3.5%, andpreferably in the range 3.5% to 10%, also has the advantage of havingantiseptic properties per se. Thus, it not only acts as an excipient,but it also acts as an active principle, in particular when treatingmucitis.

Finally, the bioadhesive therapeutic systems of the invention cancomprise between 0.1% and 1% of a sugar monohydrate, preferably lactosemonohydrate or saccharose. The presence of lactose is not, a priori,indispensable per se, provided that the concentration of milk proteinsis high. However, the presence of lactose monohydrate or saccharoseresults in a substantial modification of a step of the preparationprocess as described in EP 0 542 824-B1, which consists of eliminating agranulation step in the presence of alcohol and replacing it with awetting liquid composed of lactose or saccharose in purified water, aswill be indicated below.

This absence of ethanol has the particular advantage of enabling largescale production of the bioadhesive systems of the invention withoutusing explosion-proof apparatus, which are obligatory when alcohol ispresent in any step in an industrial process.

The bioadhesive systems of the invention are prolonged release systemsand can also be coated with a soluble layer containing the same activeprinciple with immediate release; this is particularly important withanalgesic treatments for which a double effect—immediate andprolonged—is sought.

The present invention also concerns a process for preparing a mucosalcontroled release bioadhesive therapeutic system containing at least oneactive principle, with an active principle dissolution percentage ofmore than 70% over 8 hours, comprising at least:

-   -   a step for mixing the active principle with natural proteins,        these latter representing at least 50% by weight of active        principle, and with excipients and fillers comprising at least        one hydrophilic polymer; and    -   a step for mixing with an alkali metal alkylsulphate in a        concentration in the range 3.5% to 10% by weight of the        bioadhesive therapeutic system, preferably 4% to 6%.

In one implementation, the bioadhesive therapeutic system is a prolongedrelease mucosal bioadhesive tablet and the preparation of whichcomprises the following steps:

-   -   a) a step for mixing the active principle with natural proteins,        said proteins representing at least 50% by weight of the active        principle, and with excipients and fillers comprising at least        one hydrophilic polymer;    -   b) a step for wetting the mixture obtained at a) with a        monohydrate sugar or polyol type binder;    -   c) a step for drying the mixture and sizing the grains obtained;    -   d) a step for mixing the grains obtained with an alkali metal        alkylsulphate in a concentration in the range 3.5% to 10% by        weight of tablet, preferably 4% to 6%.

In the method of the invention, the active principle or activeprinciples, if necessary mixed with methylhydroxypropylcellulose ormetolose (MHPC) is sieved with an open space of between 0.4 and 1 mm,then mixed with at least 50% by weight of natural proteins, such as milkproteins. The powder obtained is homogenized. It then undergoes wettingstep in a granulation step in which the powder is mixed with a lactoseor saccharose solution in distilled water. It is then followed by dryingto produce a residual moisture content of about 3%. It is then followedby a calibration step, mixing with the remaining excipients and by acompression step. A particular feature of the wetting liquid, lactose inwater, is that the quantity introduced during batch production is notfixed but should be determined as a function of the appearance of thegrain. There are three possibilities:

-   -   either all the wetting liquid is introduced and the subsequent        production phases of tablet are carried out conventionally by        adding excipients, as indicated in the examples below;    -   or not all of the wetting liquid is used and metolose is added        with the formulation excipients to arrive at a final        concentration (between 0.1% and 1%, preferably between 2% and 4%        of the final tablet). A typical production diagram is shown in        FIG. 1 illustrating Example 2;    -   or all of the lactose or saccharose is dissolved in half of the        theoretical quantity of purified water. All of this wetting        liquid is introduced into the mixture. The remaining half of the        purified water is used as a reserve when optimizing wetting and        can be adjusted as a function of batch size.

This latter possibility avoids the phase for compensating for themonohydrated lactose with metolose. It is particularly advantageous whenscaling up as the quantities to be introduced can be calculated byknowing the batch size without a need to known the grain appearance. Thescaling up experiments shown below indicate that the method is suitablefor large scale production both with lactose and with saccharose. Largescale dissolution tests with the composition of Example 3 demonstratethis.

A further essential characteristic of the method for preparing tabletsof the invention is adding an alkali metal alkylsulphate in step d)above in a concentration in the range 3.5% to 10% of the tablet weight,preferably in the range 4% to 6%. It is actually added at the same timeas the formulation excipients such as talc and magnesium stearate, toendow the tablets with the functions described above, in particular asregards rate of dissolution.

The invention also concerns a method for preparing a bioadhesivetherapeutic system other than tablets, such as microspheres, in which astep for adding an alkali metal alkylsulphate in the same range ofconcentration as described above is added to the preparation.

The alkali metal alkylsulpahte is preferably sodium laurylsulphate orsodium diethylsulphosuccinate. The production of pilot batches describedin the examples below used sodium laurylsulphate in a concentration of4.5%.

The method of the invention results in prolonged release bioadhesivetablets that are particularly suitable for application to the mucosa,and more particularly to the buccal mucosa.

The examples pertain to tablets containing as the active principleantifungal substances for treating buccal candidiasis, anti-infectioussubstances (AZT, aciclovir), active principles for treating pain(fentanyl) or nausea (metoclopramide). The skilled person will becapable of adapting the production of the bioadhesive therapeutic systemwith a further active principle for application to other types of mucosaand/or for other types of diseases.

For active principles with absorption, two action mechanisms, local andsystemic, can be obtained. The following can be cited: aphthae forbuccal infections, anti-infectious agents for vaginal infections,inflammation, local antalgics or opioid analgesics for pain, dryness,metoclopramide for nausea, antiulcerous agents and local bacterialinfections.

Finally, the present invention concerns the use of bioadhesivetherapeutic systems to dissolve active principles and to allow prolongedrelease as a drug for preventative, curative or maintenance treatment ofdiseases, in particular of the mucosa. More particularly, the advantageof the bioadhesive therapeutic systems of the invention is their use toprevent or treat candidosa infections of the buccal mucosa and thebioadhesive therapeutic system contains an azole as the active principlein a dose of 10 to 150 mg per tablet, preferably 25 to 75 mg per tablet.

For the treatment of other buccal infections, vaginal or globalinfections and more particularly HIV infections (human immunodeficiencyvirus), EBV (Epstein-Barr virus, infectious mononucleosis, hairyleukoplakia), CMV (cytomegalovirus), herpes simplex virus (HSV) orvaricella zoster virus (VZV), the active principles contained in thebioadhesive therapeutic systems are zidovudine, aciclovir, valacicloviror ganciclovir. The doses of aciclovir and valaciclovir are 20 to 100mg, preferably 50 mg. Doses for zidovudine and ganciclovir are 10 to2000 mg, preferably 500 to 1500 mg. The desired action is local and moreparticularly, at the place of entry of the infectious agent, but alsogeneral because of the particular mode of action of these viruses inganglionic tropism.

Bioadhesive therapeutic systems can also be used for drugs for treatingaphthae or pain. When treating pain, the systemic action is moreadvantageous, associated with local release, and is achieved with abioadhesive therapeutic system by dint of its mode of release. The lowbioavailability of fentanyl is improved by the bioadhesive form whichdissolves and releases the active principle into the buccal mucosa. Thisbioadhesive system applied to fentanyl can associate an immediate actionwith a prolonged action that is particularly advantageous in pain and inparticular for intense, resistant pain, in particular that associatedwith cancer.

The bioadhesive system of the invention is particularly advantageouswhen the active principle is fentanyl base which is an insolublemolecule and the solubility of which is improved with laurylsulphate. Arange of doses of fentanyl of 50 to 1600 μg, and preferably 200 to 1200μg, is possible with this therapeutic system, and can be adapted to thepain to be treated.

The use of the bioadhesive therapeutic systems of the invention isparticularly attractive for the patient, since prolonged release allowsa single daily administration of the bioadhesive therapeutic system andit permits local mobilization of the active principle and low systemicpassage. The various advantages of the bioadhesive therapeutic systemand in particular the tablet of the invention prepared using the methoddescribed above appear in the examples described below.

Exemplified Embodiment of the Invention EXAMPLE 1 Effect of SodiumLaurylsulphate on a Bioadhesive Tablet Dissolution Test

The solubility characteristics of miconazole in a prolonged releaseadhesive form were tested successively using a dissolution test underconventional formulation conditions as described in EP 0 542 824, undermodified conditions but without laurylsulphate then with addition ofsodium laurylsulphate to the primary grain under the conditions ofExample 2 below and FIG. 1.

1.1 Formula Without Sodium Laurylsulphate:

The dissolution test carried out in pure water produced very lowmiconazole dissolution percentages (<5%) early on (1 h and 3 h).

1.2 Formula Without Sodium Laurylsulphate and Changing the TestConditions:

Because the dissolution test was impossible in pure water and takinginto account the recommendation from EMEA (Note for guidance on qualityof modified release products), the dissolution test conditions weremodified to obtain the most discriminating in vitro test. The testretained still satisfied the demands of the Pharmacopée Européenne(Essai de dissolution des formes solides, Phée Eur 1997, 2.9.3) and wascharacterized by a dissolution medium containing 0.05% of sodiumlaurylsulphate.

1.3 Formula Containing Sodium Laurylsulphate:

After adding 4.5% of sodium laurylsulphate to the miconazole tablet, thedissolution test produced satisfactory results for a prolonged releaseform.

Comparative results for the dissolution tests for the three formulae areshown in Table I below:

TABLE I Miconazole dissolved (%) Time (h) Formula 1.1 Formula 1.2Formula 1.3 1 <5% 14.8 9.2 3 <5% 35.5 35.8 5 ND 52.2 61.1 8 ND 73.1 85.8

In formula 1.2, the dissolution test was improved over formula 1.1, butwe can conclude that release of the active principle was insufficientfor a prolonged release drug.

Formula 1.3 with sodium laurylsulphate not only allowed prolongedrelease of miconazole but also produced novel qualities (wetting,swelling and dissolving of the active principle for constant in situlocal concentrations).

EXAMPLE 2 Preparation of a Tablet Containing 50 Mg of Miconazole

a) 1.9 kg Batch:

The preparation diagram for this tablet is shown in FIG. 1. 50 mg ofmiconazole base (or 100 mg for a 100 mg tablet) was mixed with 9.2 mg ofcorn starch and 20.5 mg of methylhydroxypropylcellulose.

The mixture was then homogenized by sieving and 27.43 mg of LR85F milkproteins was added and mixed with the initial mixture. This latter wasthen wetted with a mixture of lactose monohydrate (lactose 200 Mesh inan amount of 0.39 mg in purified water). During batch production, all ofthe wetting liquid was introduced, namely 0.39 mg per 115 mg tablet,representing 0.34% by weight of the total constituents. The wetting stepwas followed by a granulation, drying and sizing step carried out underconventional conditions, to obtain the primary grain indicated in FIG.1.

A mixture of excipients was added to this primary grain: talc, magnesiumstearate, methylhydroxypropylcellulose, to which sodium laurylsulphatein a concentration of 4.5% was added after sieving.

The final mixture then underwent conventional phases of tabletcompression and packaging.

The composition of a 50 mg dose tablet and that of a 100 mg dose tabletare shown in the table below.

TABLE II composition 1 50 mg dose 100 mg dose batch Com- batch Com-position in position in mg/tablet mg/tablet % miconazole base 50.00100.00 43.50 methylhydroxypropylcellulose 20.50 41.00 17.80 Metolose90SII150000 LR85F milk proteins 27.43 54.86 23.80 corn starch 9.20 18.408.00 lactose monohydrate 0.39 0.78 0.34 (lactose 200 Mesh) sodiumlaurylsulphate 5.18 10.35 4.50 magnesium stearate 1.32 2.65 1.15 talc0.98 1.96 0.85 purified water qs qs TOTAL 115.00 230.00 100

In this composition, the milk proteins could be selected from all of theconcentrates cited above provided that they titrated at least 85% ofproteins.

Further, saccharose could be substituted for lactose under the sameconditions as Example 7 below.

b) Scale-Up: 10 kg Batch:

Industrial scale-up was carried out respecting the same composition asthat in Table II above to produce a 10 kg batch.

On a large scale, the method of FIG. 1 can be adapted and simplified:

-   -   by introducing a fixed quantity of lactose, without compensating        with metolose;    -   by carrying out a previous calculation of the quantity of water        to be introduced, which meant that the grain appearance could be        ignored, rendering the method adaptable to closed vessel        apparatus.

The dissolution tests carried out on the compositions of Example 3 belowindicate the industrial feasibility of the method on a large scale,since the results were no different from those obtained for tablets fromthe 1.9 kg batch.

EXAMPLE 3 In vitro Dissolution Test

a) Comparison of 50 mg and 100 mg/Tablet Dosed Tablets:

Release of miconazole from its galenic form and the disintegration rateof the tablet were measured in vitro using a dissolution test. The testwas carried out in a paddle apparatus rotating at 60 rpm at 37° C. in asuitable medium, following the recommendations of the PharmacopéeEuropéenne. The miconazole was assayed using HPLC technique.

The results obtained for the two types of tablets BA001-50 and BA001-100are shown in Table III below. Only the percentages of releasedmiconazole are shown in the table; indeed, the disintegrationpercentages results for the tablet were completely superimposable.

TABLE III dissolved miconazole (%) Time (h) 50 mg tablet 100 mg tablet 1h  9.2 ± 1.7  7.8 ± 0.5 3 h 35.8 ± 4.6 30.2 ± 1.3 5 h 61.1 ± 6.2 51.5 ±2.0 8 h 85.8 ± 3.5 74.4 ± 1.7

These studies show that after 8 hours, almost all of the miconazole hasbeen released from its galenic form for the 50 mg tablet and the releasewas constant. The results obtained with the 100 mg tablet were of thesame order. These release times were long, allowing prolonged release tobe envisaged in vivo into the buccal cavity, resulting in a prolongedantifungal effect. This hypothesis was verified by the phase I clinicalstudy in the healthy volunteer in Example 4 below. This study wascarried out with two doses of miconazole (50 and 100 mg). By examiningthe respective release times obtained in vitro and the minimum desiredsalivary concentrations, one of the two doses could be selected and itsadministration frequency deduced.

b) Comparison of a Laboratory Size Batch and an Industrial Size Batch.

The respective quantities of the products were as follows:

quantities (g) 50 mg miconazole tablets 1.9 kg batch 9.8 kg batch rowmaterials (17 000 tablets) (85 000 tablets) miconazole base 850.004261.00 metolose 348.5 1747.00 milk protein concentrate 466.31 2337.00corn starch 156.4 784.00 lactose monohydrate 6.63 34.00 sodiumlaurylsulphate 88.06 441.00 magnesium stearate 22.44 112.70 talc 16.6683.30 total 1955.00 9800.00

The dissolution tests obtained for the two batches were similar to thoseof FIG. 2 with more than 70% dissolution over 8 hours.

EXAMPLE 4 Results of Texturometer Bioadhesion Tests

This test was intended to compare the adhesive properties of tablets invitro.

Apparatus:

The apparatus used for this test was a texturometer (type TEC 025). Itwas composed of the following elements:

-   -   a lever arm to allow the probe to be raised and lowered;    -   200 N force sensor which measured the force necessary to        fracture the tablet;    -   a disposable plastic probe on which the tablet is fixed;    -   a steel module surmounted by a plastic 4 cm diameter        crystallizer, the base of which was constituted by a stainless        steel plate. This crystallizer will contain the medium necessary        for wetting the tablets.        Operating Procedure:    -   fix tablet to be studied on a plastic probe with cyanoacrylic        adhesive;    -   screw the probe onto the lever arm of the texturometer;    -   place deionized water in the crystallizer (about 4 ml);    -   lower the probe into the crystallizer until the tablet is        completely immersed and leave the tablet in the water to wet it        for a defined period;    -   measure the in vitro adhesivity by applying the texturometer        protocol which comprises three steps:        -   step 1: lower the probe until the tablet comes into contact            with the metal plate;        -   step 2: contact phase, which adheres the tablet to the            plate;        -   step 3: lift probe: fracture phase.

In the table below, the probe raising and lowering rates were fixed at0.25 mm/s, the wetting and contact times were fixed at 60 seconds, andthe study medium used was deionized water.

The results were as follows:

positive work (J) tests formula with lactose formula with saccharosetablet 1 4.00 × 10⁻⁴ 3.40 × 10⁻⁴ tablet 2 3.78 × 10⁻⁴ 3.18 × 10⁻⁴ tablet3 3.45 × 10⁻⁴ 2.93 × 10⁻⁴ tablet 4 4.06 × 10⁻⁴ 3.25 × 10⁻⁴ mean 3.82 ×10⁻⁴ 3.19 × 10⁻⁴ standard deviation 0.275 × 10⁻⁴  0.19 × 10⁻⁴Interpretation of Results:

The data measured by the force sensor were analyzed using TexturometerTEC v6.0 ETIA 1996 software and expressed in the form of a force(N)/time (s) curve. This software could also trace a force/distance (mm)curve. The in vitro adhesivity of tablets was evaluated by the value ofthe positive work (J) measured during the tablet fracture phase. Thiswork was represented by the area under the force/distance curve.

The higher the value, the better the bioadhesive properties of thetablet.

The results obtained under identical conditions with tablets of the samediameter allowed a comparison between different formulations.

EXAMPLE 5 In vivo Prolonged Release Study With the Tablet of theInvention

This study was carried out by means of a salivary kinetics using 18healthy volunteers and with two dosages of miconazole (50 and 100 mg).The tolerance of this galenical form was also evaluated.

The tablets of the invention were compared with a buccal gel containingmiconazole. Since the gels did not remain in the buccal cavity, they hadto be applied several times a day. The maximum salivary concentrationsof miconazole were observed immediately after application, but theactive principle was rapidly eliminated from the buccal cavity (Odds,1981, Clean Raise Rev. 1:231-232). After applying 6.25 g of buccal gel,equivalent to 125 mg of miconazole, the salivary concentrations were 5to 0.4 μg/ml from 30 min to 3 hours following application. Theadministration frequency was four applications per day.

5.1 Aims of the Study:

Principal Aim:

The principal aim of this study was to determine the salivary kineticsof miconazole from two types of prolonged release (PR) tablets, 50 or100 mg, in eighteen healthy volunteers and to compare them with thatobtained with the buccal gel (125 mg of immediate release miconazole)under the same conditions.

Secondary Aim:

The secondary aims of this study were as follows:

-   -   to determine the blood pharamokinetics of miconazole from two        types of prolonged release (PR) tablets, 50 mg or 100 mg;    -   to evaluate the clinical tolerance of bioadhesive miconazole        buccal tablets;    -   to determine the acceptability and tolerance by the subject        him/herself.        5.2 Study Scheme

A monocentric randomized cross-over phase I study in the healthyvolunteer. Eighteen subjects each received 3 types of products in adifferent order with a latency period of 8 days between eachadministration.

The 3 products administered were the 50 mg bioadhesive miconazoletablet, the 100 mg bioadhesive miconazole tablet and the 125 mg per doseimmediate release miconazole gel. The treatments were numbered 1 to 18.In each treatment, the product was blind labeled “week 1”, “week 2” or“week 3” (50 mg or 100 mg tablet or gel).

A salivary and sanguine assay of miconazole was effected prior toadministering the product. Then, a salivary and blood sample was takenat 30 minutes then 1 hour and then every hour up to 12 hours for thesaliva or up to 4 hours for the blood with a blood sample then beingtaken at 8 and 12 hours; a saliva and a blood sample were taken at 24hours.

Samples:

-   -   Salivary sample: to avoid abnormally high miconazole levels, the        tongue could not be in contact with the tablet for the 10        minutes preceding sample removal. Further, for samples removed        30 minutes after an administration, care had to be taken to wash        the subject's lips;    -   2 ml of saliva was collected in a borosilicate tube over a        period of 2 min (1 min prior to and 1 min after the given time).    -   The labeled tubes were preserved at −20° C. to await analysis.    -   Blood sample: the labeled borosolicate tubes of collected blood        were preserved at −20° C. to await analysis.

Means of Administration and Adhesion of Bioadhesive Tablets:

-   -   Means of administration: the tablet was removed from the unit        flask and placed under the upper lip in the canine fossa. It was        positioned either with the fingers or with a disposable device        that could centre the tablet in the canine fossa and facilitate        its adhesion.    -   Adhesion period: the adhesion period of tablet was noted. It was        defined as the time after which the tablet was no longer visible        in the vestibule or on the gum with a sensitive external control        carried out at the time of each sample. The circumstances of the        end of adhesion had to be specified (erosion or detachment of        the tablet). In the case of detachment, the time was noted and        the tablet had to be swallowed.

Means for Administering the Buccal Gel (in Accordance With Daktarin® 2%Buccal Gel Notice):

The dosage was 2 spoonfuls as provided with the tube of gel. The gel hadto be kept in the mouth for as long as possible (2 to 3 minutes) beforeswallowing it. Administration had to be carried out between meals ordrinks or at least 10 minutes afterwards.

Buccal Examination:

This was carried out after 10 h by the same person who carried it outprior to administering the product.

5.3 Evaluation:

a) Principal Evaluation Criterion:

Salivary pharmacokinetics of miconazole:

Miconazole was assayed blind using high performance liquidchromatography technique. The results are expressed using the normalpharmacokinetic criteria (C_(max), T_(max), AUC) and the products werecompared. The results are shown in Table IV below.

b) Secondary Criteria:

Blood Assay of Miconazole:

Miconazole was assayed blind by high performance liquid chromatographytechnique. The results were expressed using normal pharmacokineticcriteria (C_(max), T_(max), AUC) and the products were compared.

Local Clinical Tolerance of Bioadhesive Tablet:

This was evaluated by a clinical examination of the buccal mucosacarried out by the same investigator 10 hours after administration.

The tolerance was also determined for each product and on the day ofeach administration by the volunteer himself using a questionnaire (fourpossible choices: good, acceptable, modest or disagreeable: ifdisagreeable, details were provided).

Acceptability of Bioadhesive Tablet:

The volunteer determined this using a questionnaire for each product andthe day of each administration (four possible choices: good, acceptable,modest or disagreeable: if disagreeable, details were provided).

5.4 Results:

a) Salivary Concentration Obtained in vivo:

The salivary concentration results obtained over time in vivo are shownin FIG. 3 and Table IV below.

TABLE IV C_(max) T_(max)* AUC 0-12 treatment (μg/ml) (h) (μgl · h/ml)100 mg bioadhesive tablet 39.06 ± 49.29 6 78.62 ± 78.42  50 mg ofbioadhesive tablet 15.07 ± 16.21 7 42.97 ± 31.99 gel 1.61 ± 1.62  4#3.43 ± 4.14 *= mean; #corresponds to 0.5 hours after secondadministration.

These results show that the 50 mg dose tablet had a maximum salivaryconcentration of 15.07 μg/ml while it was 1.61 μg/ml for the buccal gel.The three peaks observed in FIG. 3 correspond to three administrationsof the gel just after T0, T4 and T9 while the tablets were administeredjust once. It thus appears that the salivary concentration was verysubstantially higher with the tablets compared with that obtained withthe buccal gel.

The MICs (minimum inhibiting concentration) of miconazole for Candidosaalbicans are 1 to 10 μg/ml. The salivary concentrations of more than 1μg/ml show that the gel rarely exceeded this threshold while the 50 mgbioadhesive tablet was regularly above this threshold (16 subjects outof 18 as opposed to 0 with the gel). The mean daily time during whichthe 50 mg bioadhesive tablet had salivary concentrations of more than 1μg/ml was 7.22 hours (as opposed to 0.61 hours for the gel). This meansthat the concentration ensured a sufficient pressure locally on anygerms and thus a reduced risk of the appearance of resistant strains.

b) Other Results:

The mean tablet adhesion time was 15 hours for the 50 and 100 mgtablets.

The mean blood concentration was 0.035 μg/ml for the gel, as opposed to0.020 μg/ml for the 50 mg tablet and 0.013 μg/ml for the 100 mg tablet.

The local and general tolerance was good; the bioadhesive tablets werepreferred in 17 cases out of 18 (as opposed to 1 in 18 for the gel).

Flavour proved to be a particularly important criterion in a spontaneousquestionnaire regarding the gel (13 cases out of 18 indicated a poorflavour as opposed to 2/18 for the 100 mg tablet and 1/18 for the 50 mgtablet).

EXAMPLE 6 In vitro/in vivo Correlation

FIG. 4 shows the cumulative salivary amounts of miconazole (μg/ml) as afunction of the in vitro dissolution test carried out over 8 hours. Thein vitro dissolution test is shown along the abscissa in the form of theratio of the percentage of dissolved miconazole with respect to thepercentage of miconazole in the tablet. This figure clearly indicatesthat everything released from the tablet was found in the saliva.Deglutition was considered to be constant and systemic passage was zero.In the second portion of the curve, in which the slope increased, moremiconazole was assayed in the saliva than was released form the tablet.

This result is particularly important. Indeed, the most likelyhypothesis that can be proposed to support these results and in theabsence of systemic passage is that the active principle is beingreleased from the buccal mucosa. In the first phase, then, deglutitionoccurs with a loss of active principle, associated with storage of theactive principle in the buccal mucosa. This storage can be explained byan equilibrium of the active principle in micelles formed by thelaurylsulphate, which can then precipitate out and adhere to the mucosa;it is then released as the saliva is secreted.

Then, the tablets of the present invention have the advantage not onlyof producing no systemic passage but that the buccal mucosa forms areservoir for the active principle. This explains the fact that taking50 mg of active principle once in 24 hours is surprisingly sufficientwhile Daktarin® buccal gel is administered daily in an amount of 500mg/day.

EXAMPLE 7 Different Compositions Produced From the Bioadhesive Systemsof the Invention

7.1 Modifications to Active Principle:

Composition 1 of Table II in Example 2 was repeated with other activeprinciples under the following conditions:

compo- concen- admin- sition tration istration authorized n° activeprinciple mg/tablet method concentration range 1 miconazole 50 buccal or  2-100 vaginal 2 aciclovir 50 buccal or   2-100 vaginal 3 AZT 700vaginal   10 to 2000 preferably  500 to 1500 4 methoclopramide 100buccal   20-100 5 fentanyl 1 buccal 0.05-1.6 6 laurylsulphate 5.18buccal or   1-100 vaginal7.2 Replacing Lactose With Saccharose:

In all of the compositions, the 0.39 g per tablet of lactose could besubstituted with 29.59 g±3 of saccharose.

The results for the dissolution tests and adhesivity tests were similar.

7.3 Production of a Rapid and Prolonged Release Tablet:

The above compositions could be coated when the therapy required a rapidrelease layer of the same active principle.

The geometry of these two layers—rapid release and prolonged release—wasnot important and could be achieved using any technique that is known tothe skilled person provided that the bioadhesive qualities of thetablets of the invention were retained.

The present invention provides a preparation method and prolongedrelease bioadhesive tablets which enable administration of an activeprinciple in an amount of 24 hours in a dose of close to 10 times lowerthan the reference galenical form proposed now. Further, the dissolutiontest, namely more than 70% over 8 hours, is adapted to the frequency ofadministration. In the case of miconazole, not only a low systemicpassage is observed but, further, it would appear that the in situconcentrations ensure local antimycosal cover over a prolonged period.The form is adhesive for a prolonged period and is well tolerated, theflavour and acceptability are improved, rendering the invention usefulclinically and extrapolatable to many active principles.

More generally, the present invention can be adapted to othermucoadhesive microsphere or nanosphere systems.

1. A prolonged release bioadhesive therapeutic system containing atleast one active principle, having an active principle dissolutionpercentage of more than 70% over 8 hours, comprising quantities ofnatural proteins representing at least 50% by weight of active principleand at least 20% by weight of said bioadhesive therapeutic system,between 10% and 20% of a hydrophilic polymer, compression excipients,and comprising between 3.5% and 10% of an alkali metal alkylsulphate andbetween 0.1% and 1% of a monohydrate sugar.
 2. A bioadhesive therapeuticsystem according to claim 1, wherein said bioadhesive therapeutic systemis a mucoadhesive tablet.
 3. A bioadhesive therapeutic system accordingto claim 2, wherein the alkali metal alkylsulphate is sodiumlaurylsulphate or diethylsulphosuccinate.
 4. The bioadhesive therapeuticsystem according to claim 3, in the form of a tablet in which thealkylsulphate is sodium laurylsulphate in a concentration of 3.5% to10%, of the total weight of the compounds in the tablet.
 5. Thebioadhesive therapeutic system according to claim 2, in which the sugarmonohydrate is lactose monohydrate or saccharose.
 6. The bioadhesivetherapeutic system according to claim 1, wherein the compressionexcipients contain corn starch.
 7. The bioadhesive therapeutic systemaccording to claim 1, in which one of the active principle is anantifungal from the broad spectrum azole family.
 8. The bioadhesivetherapeutic system according to claim 7, in the form of a tablet inwhich the azole is miconazole present in a dose of 10 to 150 mg pertablet.
 9. The bioadhesive therapeutic system according to claim 7, inwhich the active principle is a broad spectrum azole, in associationwith a further active principle selected from: a polyene type antifungalwith a different spectrum; an analgesic; a salivation agent; anantiseptic; a salivary substitute; an anti-inflammatory (corticoids); anantibiotic; thalidomide; or a mixture thereof.
 10. The bioadhesivetherapeutic system according to claim 9, in which the second activeprinciple is a polyene in a dose of 10 to 100 mg per tablet.
 11. Thebioadhesive therapeutic system according to claim 9, further comprising0.1% to 10% by weight of anaesthetic and/or 0.1% to 10% by weight ofsalivation agent.
 12. The bioadhesive therapeutic agent according toclaim 1, in which the active principle is an antiseptic.
 13. Thebioadhesive therapeutic system according to claim 12, in which theantiseptic is sodium laurylsulphate in a minimum concentration of 3.5%by weight.
 14. The bioadhesive therapeutic system according to claim 1,in which the active principle is an antiviral that is active for HSVviruses (herpes) VZV (varicella zoster virus), Epstein-Barr virus(infectious mononucleosis, hairy leukoplakia), cytomegalovirus.
 15. Thebioadhesive therapeutic system according to claim 14, in which theantiviral is present either in an amount of 20 to 100 mg or 10 to 2000mg.
 16. The bioadhesive therapeutic system according to claim 1, inwhich the active principle is an antiviral active against HIV virus(human immunodeficiency virus).
 17. The bioadhesive therapeutic systemaccording to claim 16, in which the active principle is present in anamount of 10 to 2000 mg per bioadhesive therapeutic system.
 18. Thebioadhesive therapeutic system according to claim 1, in which the activeprinciple is an insoluble analgesic from the opioid family.
 19. Thebioadhesive therapeutic system according to claim 18, in which theinsoluble anagesic from the opioid family is present in an amount of 50to 1600 micrograms per bioadhesive therapeutic system.
 20. The methodfor preparing a prolonged release mucosal bioadhesive therapeutic systemcontaining at least one active principle, with a dissolution percentageof the active principle that is more than 70% over 8 hours, comprisingat least: mixing at least one active principle with natural proteins,these latter representing at least 50% by weight of the activeprinciple, and with excipients and fillers comprising at least onehydrophilic polymer; and further mixing with an alkali metalalkylsulphate in a concentration range 3.5% to 10% by weight of theextended release mucosal bioadhesive therapeutic system.
 21. A methodpreparing a bioadhesive therapeutic system tablet comprising thefollowing steps: a) mixing at least one active principle with naturalproteins, these latter representing at least 50% by weight of the activeprinciple, with excipients and fillers comprising at least onehydrophilic polymer; and b) wetting the mixture obtained at a) with amonohydrate sugar or polyol; c) drying the mixture and sizing the grainsobtained; and d) further mixing with an alkali metal alkylsulphate in aconcentration in the range 3.5% to 10% by weight of the tablet.
 22. Themethod according to claim 21, in which the wetting step b) is followedby a granulation step carried out in the absence of alcohol.
 23. Themethod according to claim 21, in which the sugar monohydrate is lactosemonohydrate in a concentration in the range 0.1% to 1%.
 24. The methodaccording to claim 21, in which the alkali metal alkylsuiphate is sodiumlaurylsulphate or sodium diethylsulphosuccinate.
 25. The methodaccording to claim 21, in which the active principle or activeprinciples can, if necessary, be associated with a further activeprinciple selected from: a polyane type antifungal with a differentspectrum; analgesic' a salivation agent; an antiseptic; a salivarysubstitute; an antl-inflammitory (corticolds); an antibiotic'thalldomide; or mixtures thereof.
 26. A method for treating viralinfections which comprises administering to a patient in need thereof abioadhesive therapeutic system according to claim
 14. 27. The methodaccording to claim 26, in which the active principle is an antiviralanti-infectious agent that is active for HSV viruses (herpes), VZV(varicella zoster virus), Epstein-Barr virus (infectious mononucleosis,hairy leukoplakia), cytomegalovirus.
 28. The method according to claim26, in which the active principle is an antiviral anti-infectious agentthat is active against HIV virus (human immunodeficiency virus) and ispresent in an amount of 10 to 2000 mg per bioadhesive therapeuticsystem.
 29. A tablet according to claim 4, in which the sodiumlauryisuiphate is in a concentration of 4% to 6% of the total weight ofthe compounds in the tablet.
 30. A bioadhesive therapeutic systemaccording to claim 7, in which the antifungal from the broad spectrumazole family is selected from the group consisting of miconazole,clotrimazole, ketoconazole, fluconazole, itraconazole, isoconazole,econazole, saperconazole, genaconazole, terconazole, butoconazole,tioconazole, oxiconazole, bifonazole, fenticonazole, omoconazole,sertaconazole and sulconazole.
 31. The bioadhesive therapeutic systemaccording to claim 8, in which the micoazole is present in a dose of 25to 75 mg per tablet.
 32. The bioadhesive therapeutic system according toclaim 8, in which the miconazole is present in a dose of 50 mg pertable.
 33. The bioadhesive therapeutic system according to claim 10, inwhich the polyene is in a dose of 20 to 90 mg.
 34. The bioadhesivetherapeutic system according to claim 14, in which the antiviral isacyclovir, valaciclovir, zidovudine or ganciclovir.
 35. The bioadhesivetherapeutic according to claim 34, in which the aciclovir andvalaciclovir are present in an amount of 50 mg, and the zidovudine andganciclovir are present in an amount of 500 to 1500 mg.
 36. Thebioadhesive therapeutic system according to claim 16, in which theantiviral is zidovudine (AZT).
 37. The bioadhesive therapeutic systemaccording to claim 17, which is a vaginal system.
 38. The bioadhesivetherapeutic system according to claim 17, in which the active principleis present in an amount of 500 to 1500 mg.
 39. The bioadhesivetherapeutic system according to claim 18, in which the insolubleanalgesic is fentanyl.
 40. The bioadhesive therapeutic system accordingto claim 39, which the fentanyl is an insoluble base.
 41. Thebioadhesive therapeutic system according to claim 39, in which thefentanyl is present in an amount of 200 to 1200 micrograms.
 42. Themethod according to claim 20, in which the alkali metal sulphateconcentration is in the range of 4% to 6%.
 43. The method according toclaim according to claim 21, in which the alkali metal sulphateconcentration is in the range of 4% to 6%.
 44. The method according toclaim 27, which the antiviral anti-infectious agent is acyclovir orvalaciclovir present in an amount of 20to 100mg per therapeutic systemor AZT present in an amount of 10 to 2000 mg per therapeutic system. 45.The method according to claim 44, in which the AZT is present in anamount of 500 to 1500 mg per therapeutic system.
 46. The methodaccording to claim 28, in which the antiviral anti-infectious agent isAZT present in an amount of 10 to 2000 mg per therapeutic system. 47.The method according to claim 46, in which the AZT is present in anamount of 500 to 1500 mg per therapeutic system.
 48. A method fortreating diseases of the mucosa which comprises administering to apatient in need thereof, a bioadhesive therapeutic system according toclaim 1, wherein said active principle is miconazole present in a dosageof 25 to 75 mg per tablet.